This project explores pharmacokinetic and pharmacodynamic approaches to developing new treatments for drug dependence and reduction of HIV transmission risk behaviors, with a current focus on cocaine, marijuana, and nicotine dependence. Many subjects are at high risk for contracting and spreading HIV infection. HIV transmission risk behaviors are assessed and HIV testing and risk reduction counseling are offered to all subjects. The pharmacokinetic approach being studied is blunting the rate of onset of drug effect by enhancement of drug metabolism. Rate of onset of drug effect is considered an important influence on the reinforcing effects of drugs. The influence of rate has treatment implications, in that drugs from the same pharmacologic class but with slower rate of onset may have therapeutic efficacy without themselves inducing addiction. Enhancement of cocaine metabolism is being studied using butyrylcholinesterase (BChE), a major cocaine-metabolizing enzyme in humans. Increased BChE activity might reduce cocaine concentrations and thus cocaine's effects, with possible therapeutic benefits. Pharmacodynamic approaches being studied include modulation of brain neurotransmitters and blockade of relevant neurotransmitter receptors. The former approach is being implemented using transcranial magnetic stimulation (TMS), in collaboration with the Maryland Psychiatric Research Center. TMS involves projecting pulsed magnetic fields through the skull into the brain, where they alter neuronal firing and change levels of neurotransmitters. TMS is a safe, non-invasive way of modulating activity in brain circuits that mediate drug craving and reward, thus offering a potential treatment for drug addiction. Pilot studies are planned to evaluate the safety and efficacy of TMS in users of cannabis, cocaine, and nicotine. The second approach is being implemented, in collaboration with the Chemistry &Drug Metabolism Section and the Maryland Psychiatric Research Center, by evaluating the effects in humans of an experimental compound, rimonabant, which acts as an antagonist at the cannabinoid 1 (CB1, marijuana) receptor in the brain. Previous studies found that rimonabant blocked the effects of smoked marijuana, without altering THC plasma pharmacokinetics, suggesting that CB1 receptors play an important role in mediating the effects of marijuana in humans. Recently terminated studies evaluated the interaction of rimonabant with oral THC and its safety and efficacy in patients with schizophrenia.